Selective estrogen receptor-2 (ER2) targeting may be a novel therapeutic target for the development of therapies for a range of conditions including cognitive impairment and age- related ovarian failure (menopause). There are plausible mechanisms by which ER2 receptor stimulation could lead to improved cognition, feelings of well being, reduced risks for cognitive impairment, and improved vasomotor symptoms. A formulation composed of rationally-selected ER2-selective phytoestrogens (phytoSERMs) was developed that provides a greater effect than the various nutraceuticals that are mixed with both ER1 and ER2 selective components. This new formulation is composed of rationally-defined content that induces synergistic rather than antagonistic effects on estrogen receptors and could likely generate salutary therapeutic effects. The formulation enhances ER2 responses by adding equol to genistein and daidzein moderating potential influences of inter- individual differences in the production of equol. Three major potential advantages of the formulation are: (1) reduction of antagonistic interactions that occur in complex soy-derived isoflavone preparations; (2) minimization of adverse effects associated with ER1 activation in reproductive tissues; (3) potential health benefits in pathologic conditions mediated by ER2. Thus, it may serve as an alternative to current estrogen therapies. We are proposing a phase I to IIa pilot development program for this ER2 specific phytoSERM combination for post-menopausal women in the 50 year-old range as the first to human studies. The phase I bridging study uses ascending doses in 3 consecutive panels of 9 participants to assess tolerability, pharmacokinetics, and potential safety with 4 weeks exposures. The phase IIa proof of concept dose-ranging, placebo-controlled trial will assess tolerability, safety, and potential efficacy over 12 weeks. Given that soy isoflavone extracts are available as dietary supplements, and that the compounds are 'generally recognized as safe' (GRAS, under FDA regulations), we expect this phytoSERM combination to be very well tolerated with a benign adverse event profile over 12 weeks. Because soy derived isoflavones sold as dietary supplements were not subject to formal drug development, and that this is a new combination of phytoSERMs, we believe that a careful, stepwise development approach for the phytoSERMs will provide systematic information, better benefit clinical knowledge, and provide a platform for future development. PUBLIC HEALTH RELEVANCE: One of the largest unmet needs in menopausal women's health is an estrogen therapy that is both safe and effective. We have developed a formulation of phytoestrogenic molecules, that we term PhytoSERMs, which targets estrogen receptor beta. This study will determine the best dose, safety and tolerance of PhytoSERMs in peri to menopausal women experiencing hot flashes. We will also conduct a pilot analysis to determine the efficacy of PhytoSERMs to significantly reduce hot flashes.